Submissions for variant NM_004360.5(CDH1):c.1360G>A (p.Val454Ile)

gnomAD frequency: 0.00003  dbSNP: rs587780112

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328169	SCV004035107	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-03	reviewed by expert panel	curation	The c.1360G>A (p.Val454Ile) variant results in a conservative missense change in the Cadherin 3 domain of CDH1. This variant was observed in 4 in 152,164 alleles in the gnomAD v3.1.2 population database. However, this variants has also been observed in more than 10 individuals without GC, DGC, gastric SRC tumours or LBC and whose families do not suggest HDGC (BS2). In summary, this variant meets criteria to be classified as Likely Benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 05/22/2023)
GeneDx	RCV000212369	SCV000149749	uncertain significance	not provided	2022-03-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15235021, 22850631)
Ambry Genetics	RCV000115840	SCV000214246	likely benign	Hereditary cancer-predisposing syndrome	2018-11-15	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226677	SCV000288430	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-28	criteria provided, single submitter	clinical testing
Counsyl	RCV000226677	SCV000785257	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2017-06-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212369	SCV000888021	uncertain significance	not provided	2023-08-04	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals and families with breast cancer (PMIDs: 36436516 (2023), 33471991 (2021), 25186627 (2015)), as well as healthy, unaffected individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CDH1)). The frequency of this variant in the general population, 0.00011 (4/35440 chromosomes in Latino/Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000115840	SCV000911482	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 454 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with CDH1-related disorders in the literature. This variant has been identified in 6/246246 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Sema4, Sema4	RCV000115840	SCV002529060	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-17	criteria provided, single submitter	curation
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000226677	SCV003926783	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS2_Supporting (PMID: 30311375)
Myriad Genetics, Inc.	RCV000226677	SCV004020037	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-03-07	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.